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Sleep Medicine Reviews xxx (2009) 1–12

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Sleep Medicine Reviews

journal homepage: www.elsevier .com/locate/smrv

CLINICAL REVIEW

The role of environmental light in sleep and health: Effects of ocular agingand cataract surgery

Patricia L. Turner a,*, Eus J.W. Van Someren b,1, Martin A. Mainster c,2

a Department of Ophthalmology, University of Kansas School of Medicine, 7400 State Line Road, Prairie Village, KS 66208-3444, USAb Netherlands Institute for Neuroscience, an institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlandsc Department of Ophthalmology, University of Kansas School of Medicine, 7400 State Line Road, Prairie Village, KS 66208-3444, USA

a r t i c l e i n f o

Article history:Received 2 March 2009Received in revised form6 November 2009Accepted 6 November 2009

Keywords:AgingCircadianChronodisruptionCrystalline lensHypothalamic–pituitary–adrenal axisInsomniaIntraocular lensLightMelatoninRetinal ganglion photoreceptor

* Corresponding author. Tel.: þ1 913 345 0596; faxE-mail address: [email protected] (P.L. Turner).

1 Tel.: þ31 20 5665500; fax: þ31 20 6961006. e.va2 Tel.: þ1 913 345 0596; fax: þ1 913 345 0597. mm

1087-0792/$ – see front matter � 2009 Elsevier Ltd.doi:10.1016/j.smrv.2009.11.002

Please cite this article in press as: Turner Psurgery, Sleep Medicine Reviews (2009), do

s u m m a r y

Environmental illumination profoundly influences human health and well-being. Recently discoveredphotoreceptive retinal ganglion cells (pRGCs) are primary mediators of numerous circadian, neuroen-docrine and neurobehavioral responses. pRGCs provide lighting information to diverse nonvisual (non-image-forming) brain centers including the suprachiasmatic nuclei (SCN) which serve as the body’smaster biological clock. The SCN exert functional control over circadian aspects of physiology. The timingand strength (amplitude) of SCN rhythmic signals are affected by light exposure. Light deficiency mayattenuate SCN function and its control of physiological and hormonal rhythms which in turn can result ina cascade of adverse events. Inadequate pRGC photoreception cannot be perceived consciously, but mayaggravate many common age-associated problems including insomnia, depression and impairedcognition. In this review we (1) summarize circadian physiology, emphasizing light’s critical role as themost important geophysical timing cue in humans; (2) analyze evidence that typical residential lightingis insufficient for optimal pRGC requirements in youth and even more so with advancing age; (3) showhow ocular aging and cataract surgery impact circadian photoreception; and (4) review some of thediverse morbidities associated with chronodisruption in general and those which may be caused by lightdeficiency in particular.

� 2009 Elsevier Ltd. All rights reserved.

Introduction

Retinal rod and cone photoreceptors send conscious visualinformation through retinal ganglion cells and the lateral genicu-late nuclei to the visual cortex. In 2002, a subset of retinal ganglioncells (<1% in humans) were identified as photoreceptors them-selves.1 These photosensitive retinal ganglion cells (pRGCs) trans-mit information through the retinal–hypothalamic tract synapsingdirectly on neurons in the suprachiasmatic nuclei (SCN) and othernonvisual brain centers.2 pRGCs express the blue light sensitivephotopigment melanopsin.3 Approximately 3000 pRGCs cells pereye form a light sensitive network that spans the retina. Peakabsorption of isolated pRGCs and melanopsin is w480 nm.1 Humannocturnal melatonin suppression is maximally sensitive atw460 nm.4,5 These maxima lie within the blue portion of thevisible spectrum. pRGCs mediate a host of nonvisual effects with

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a blue-shifted sensitivity quite different from longer (redder)wavelengths optimal for conscious vision, as shown in Fig. 1.6,7

pRGCs detect ambient illumination allowing optimal physiologicaland neurobiological responses.1,6,8,9 Additional unique features ofpRGCs include resistance to bleaching,3 sustained signals with lightthresholds significantly higher than those required for consciousvision,2,3,10 bistability,10a seasonal light adaptability and lack ofspatiotemporal resolution.11 Deficient pRGC photoreception cannotbe perceived consciously.12

Relevant circadian physiology

In mammals the master circadian clock resides within thepaired suprachiasmatic nuclei of the anterior hypothalamus.2 TheSCN originate daily patterns of most physiologic and hormonalprocesses,13,14 timing events to allow preparation for anticipatedmetabolic and physical activities.15,16 Prior to habitual awakeningthe SCN initiate actions critical in transitioning from sleep towakefulness including hepatic and adrenal stimulation whichincreases serum glucose and produces a morning cortisol surge.15,16

Morning sunlight increases brain serotonin levels elevating mood,17

ental light in sleep and health: Effects of ocular aging and cataract

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Fig. 1. The spectral sensitivity for unconscious circadian photoreception (melatoninsuppression, lmax w 460 nm), conscious dim light vision (scotopic luminous efficiency,lmax w 506 nm) and conscious bright light vision (photopic luminous efficiency, lmax

w 555 nm). Also shown is the amount of light eliminated by a 30 diopter ultraviolet(UV)-only blocking or blue-blocking intraocular lens (IOL). The area between thecurves is the amount of light lost to circadian and dim light vision when IOL trans-mission is decreased by visible light absorbers in blue-blocking IOLs.

Nomenclature

ACTH adrenocorticotropin hormoneCNS central nervous systemCRH corticotropin-releasing hormoneHPA hypothalamic–pituitary–adrenalIOL intraocular lensLAN light-at-night5-HT serotoninpRGC photoreceptive retinal ganglion cellSAD seasonal affective disorderSCN suprachiasmatic nucleiSNS sympathetic nervous systemUV ultraviolet

P.L. Turner et al. / Sleep Medicine Reviews xxx (2009) 1–122

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vitality and core body temperature. Peak cognition occurs as theday progresses and the SCN begin active inhibition of cortisolrelease for recovery from its morning peak.15 By evening the SCNtrigger initial secretion of the hormone melatonin which reducesalertness, lowers body temperature and promotes sleepiness.Within the first hours of slumber, cortisol continues to decline toa healthful daily nadir18 while serum melatonin rises maximally.Two other hormones, prolactin and growth hormone, increaseduring sleep.14,15

These and other processes occur in an invariant sequencethroughout the SCN-controlled cycle which repeats daily,synchronized with the 24 h geophysical day under normallyentrained conditions but at a typically non-24 h fixed inheritedindividual-specific period under experimental conditions withoutenvironmental cues.2 The average human cycle was determined tobe 24.2 h in one specific experimental protocol called ‘forceddesynchrony’.19 The molecular systems controlling the self-sustaining SCN clock oscillation have been studied extensively.Similar oscillatory mechanisms are present in most cells of thebody.13,20 These peripheral cell oscillations quickly decay intodesynchrony without constant temporal alignment providedexclusively by the SCN via its neural, hormonal and possiblythermal signals.13,15,20 Proper SCN functioning is critical to goodhealth due to its vital roles including control of sleep–wake cycles,hormonal and metabolic rhythms, and synchronization of internalbiological with external geophysical time thereby assuringtemporal alignment within and between organs.13,15,21,22 Withoutunambiguous SCN signals peripheral organs can become tempo-rally uncoupled resulting in metabolic and biochemical disarray,flattening otherwise robust rhythm amplitudes.15 This internalchronodisruption has been proposed to increase the risk of variousdiseases.16,20,22–29

Neither human SCN function nor its responses to different lightsources can be measured directly so indirect assessments ofactivity, physiology or hormone levels are required. The hormonemost closely associated with SCN function is melatonin, theprimary product of the pineal gland.30 SCN neurons controlmelatonin amplitudes by suppressing or actively stimulating31 itspineal synthesis at appropriate times via a circuitous multi-synaptic sympathetic pathway.30,32 Melatonin is secreted duringthe dark phase of the light–dark cycle in normally entraineddiurnal (day-active) humans so its daytime levels are low.14 Duringthe dark phase, however, the normal nocturnal melatoninsynthesis may be quickly suppressed by the SCN response toocular light exposure depending on its intensity, spectrum, andduration.30,33,34 Therefore darkness is required for melatonin

Please cite this article in press as: Turner PL, et al., The role of environmsurgery, Sleep Medicine Reviews (2009), doi:10.1016/j.smrv.2009.11.002

production during the proper phase of the SCN cycle. Nocturnalsuppression of melatonin synthesis by light is the acceptedsurrogate for determining the efficacy of various light sources andexposures at producing the array of nonvisual light-mediatedeffects.35 The amplitude (peak-nadir range) of daily melatoninlevels is determined by and has been considered to be a proxy forSCN function.31,32 Higher peak nocturnal melatonin values (greaterdaily amplitude) would signify robust SCN signal output for therange of physiological processes it controls. Additional proxiesfor SCN function include the phase relations of hormones, bodytemperature, activities within the environmental light–dark cycle,and the fluctuation characteristics, fragmentation and day-by-dayvariations in waveform, phase, and amplitude of activityrhythms.29,36–39

Melatonin serves numerous functions.30 Its small lipophilicnature facilitates blood–brain barrier penetration and a ubiq-uitous dissemination that provides widespread hormonaltiming signals and local effects. Melatonin is one of the mostpotent antioxidants known. Each melatonin molecule mayscavenge up to 10 free radicals in a cascade extending to itssecondary, tertiary and quaternary metabolites.40 Serummelatonin levels contribute significantly to total plasma anti-oxidant capacity.41 Melatonin has numerous additionalproposed health benefits some of which are neuroprotection,anti-aging, immunomodulation, cardiovascular and oncostaticproperties.30

Nocturnal plasma melatonin concentrations (amplitudes) arehighest at about 3 years of age reaching a mean peak value of about330 pg/mL.42 As body weight increases in adolescence, thismaximum declines to approximately 65 pg/mL. It remains contro-versial whether there is further age-related decline in nocturnalmelatonin amplitude after puberty. Some studies report thisdecrease in melatonin and other hormones43 whereas others showthat elderly adults screened for good health may retain relativelyyouthful hormonal production.44 Low melatonin levels are found innumerous disease states30,45–49 while relatively preserved ampli-tudes occur in healthful advanced age.50,51


Fig. 2. Typical illuminances encountered in modern society and natural environmentsfrom various sources54,88,89 and verified independently when feasible using twodifferent light meters in a horizontal working plane 750 mm above floor level (ExtechInstruments Corporation, Waltham, MA, USA; Model 403125 Light ProbeMeter andModel EA30s). The unit lux (photopic) is used to facilitate illuminance comparisons. Acircadian lux would be more accurate for our discussion of pRGC photoreception butthis new unit has yet to be standardized and adopted.189,191

*Light levels in seasonal affective disorder phototherapy (SAD Rx) are typically 2,500lux for 2 hours/day or 10,000 lux for 30 minutes/day.57

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The critical role of light in circadian function

Short wavelengths optimally mediate non-image-forming responses

Skylight was probably the evolutionary stimulus for pRGCphotoreception. The dominant wavelength of skylight is 477 nm(blue),52 close to pRGC’s peak sensitivity. Outdoor illumination canexceed 100,000 lux, as shown in Fig. 2. With the advent of electricityand artificial lighting, industrialized society moved indoors isolatedfrom traditional environmental light–dark extremes. Modernlighting provides at best 5% of natural light intensities11,53 and itslonger (redder) wavelength spectra are less efficient for pRGCphotoreception.54 Unconscious pRGC photoreception requires muchhigher light levels than those needed for conscious vision.1,2,10 Theeffectiveness of a specific light exposure at producing pRGC medi-ated biologic effects depends on its intensity, duration and spec-trum.34 Brighter longer light exposures from sources richest in bluewavelengths most efficiently produce any of a wide range of pRGCmediated effects including melatonin suppression,4,5 photo-entrainment,55 thermoregulation,8 improved nocturnal sleepquality,56 heart rate variability,8 treatment of nonseasonal57 orseasonal depression,58 enhanced mood/well-being,59 vitality,60

alertness,8 cognition,9 reaction time and vigilance.6

Clock resetting by bright light

Daily resetting of the master pacemaker is required tosynchronize (entrain) endogenous SCN periods which otherwiseusually differ from the 24 h geophysical day–night cycle. Entrain-ment is defined as the alignment of internal with external time byenvironmental timing cues (zeitgebers). Environmental light is thestrongest and most important human zeitgeber.33,34 It is perceivedonly by the eyes in mammals.1 Sufficient well timed light exposurenot only provides optimal timing cues but also enhances under-lying SCN function.23,33,61–63 The effectiveness of a particular lightexposure for altering the timing (phase) of the endogenous SCNcycle (photoentrainment) depends on its delivery time relative tothe circadian rhythm’s phase.34 Suprathreshold early morning lightexposure advances while evening light delays the SCN’s phase.

Light insufficient for photoentrainment leads to free-running

Insufficient or absent34,64 timing cues allow the SCN’s endoge-nous rhythm to cycle independently of day–night cycles unless oruntil it receives an external stimulus sufficient to alter its inherentperiod. Repetitive cycling without daily resetting is termed free-running. Most totally blind individuals display free-running orabnormal circadian rhythms.34,65 However, some visually blind (noconscious light perception) individuals retain normal unconsciouspRGC photoreception and sufficient light exposure allows effectivephotoentrainment.66 New definitions of blindness are needed todistinguish between individuals with and those without pRGCphotoreception. The latter suffer the added disability of periodicextreme circadian desynchrony resulting in severe daytimedrowsiness from increased circadian sleep propensity and surgingdaytime melatonin67 with incessant insomnia due to circadianalerting during the geophysical night.68 This condition is compa-rable to a lifetime of recurrent profound jetlag, and experienced asalmost as disabling as blindness itself.69

The importance of light and photoentrainment is highlighted byobservations that people free-run after bilateral enucleation(surgical eye removal; no possibility of pRGC photoreception) evenwhen they are exposed to all nonvisual zeitgebers including regularmeal, work and social schedules and awareness of time.34 Blindpeople with intermittent insomnia and daytime napping67 who


receive sufficient light exposure should be suspected of free-runningand typically entrain with daily exogenous melatonin takenevenings at the same time before bedtime, improving their quality oflife70 and possibly reducing risks of early mortality that are associ-ated with visual loss.71–75 Fortunately, entrainment by exogenousmelatonin in totally blind individuals has been shown to improvesleep indices as well as entrain pituitary–adrenal activity, loweringcortisol nadirs and increasing amplitudes.76 Other approaches fornon-photic clock entrainment that have shown some efficacy inrhythm-disturbed Alzheimer patients have not yet been evaluatedin the blind.77,78 Unfortunately, lacking pRGC photoreceptionpermanently excludes totally blind individuals from experiencingthe acute direct and immediate benefits of bright light including theenhancement of mood,17 cognition,9,59 increased alerting, reducedsleepiness79 and light-mediated autonomic effects,8,80 the long-term consequences of which remain unknown.

Aging and artificial lighting predispose to circadian lightdeficiency

Age progressively limits pRGC photoreception even with normalvision

Regardless of visual acuity, human crystalline lens aging causesa progressive loss of light transmission particularly for shorter(bluer) wavelengths below 500 nm that are most valuable forcircadian photoreception.81 Pupillary area also decreases (miosis)


Fig. 3. Circadian photoreception relative to a 10 year old phakic eye for individuals atdifferent ages with a crystalline lens or with either a 30 diopter ultraviolet (UV)-onlyblocking (Tecnis, Abbott Medical Optics, Santa Ana, CA, USA) or blue-blocking (Alcon,Fort Worth, TX, USA) IOL. Age-related decreases in pupillary area and crystalline lenstransmittance reduce circadian performance in individuals who have not had cataractsurgery. Age-related decreases in pupillary area reduce circadian performance inindividuals who have had cataract surgery. Circadian performance improves aftercataract surgery regardless of age, but improvements are highest in individuals withcolorless UV-only blocking IOLs that do not reduce blue light transmission to theretina.


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with senescence, further reducing retinal illumination.82,83 Bothfactors produce progressive age-related losses in circadian photo-reception11 as presented in Table 1, which also shows the increaseor decrease in illumination needed by one age group to achievecircadian photoreception equivalent to another age group.11 Ourcalculations were performed relative to a 10 year old because thisage represents a lifetime maximum for retinal illuminance basedon crystalline lens transmission and pupillary diameter. Veryelderly individuals retain only 10% of a 10 year old’s photoreceptionand therefore require ten times brighter exposures from identicallight sources to maintain youthful circadian performance. Fig. 3displays the uniform decline in circadian photoreception overdecades and its improvement following cataract surgery usingvarious intraocular lenses (IOLs). Rod photoreceptor and retinalganglion cell populations decline with aging, but cone photore-ceptor populations remain relatively stable.84,85 The effect of agingon retinal ganglion photoreceptor populations is not currentlyknown. Glaucoma is associated with ganglion cell losses, but pRGCswere resistant to ocular hypertension in one experimental rodentstudy.86 Photoreceptive losses shown in Table 1 will be under-estimated if (1) pRGC populations decline with aging or, are lostdue to ocular disease,11 or (2) ocular media clarity is reduced orvisible light blocking filters are used.7

Human circadian thresholds exceed average residential lightinglevels

Home illumination averages 100 lux or less.32,53,87 Typicalenvironmental illuminances are shown in Fig 2.54,88,89 Residentiallighting is dim compared to natural lighting.90 Additionally, cornealirradiance is typically only 10–20% of values reported for horizontalsurface measurements.53,90,91 Minimum daily light exposurenecessary for nonvisual photoreception varies with numerousintrinsic and extrinsic factors.11 For example, poorly timed, dimmer,blue wavelength-deficient light exposures require longer durationsto produce any specific nonvisual pRGC mediated effect in olderindividuals assuming the pRGC threshold is exceeded.

Most human studies of photic neurobiological effects employone or more physiologically artificial techniques including headstabilizing chin rests, pharmacologic pupillary dilation,92 mono-chromatic light sources and monitored fixation directed at oradjacent to light sources for many hours. Circadian photoreceptive

Table 1Comparative circadian photoreception at different ages in phakic eyes.a

10 yrs 15 yrs 25 yrs 35 yrs 45 yrs 55 yrs 65 yrs 75 yrs 85 yrs 95 yrs

10 yrs 1 0.92 0.82 0.64 0.50 0.36 0.26 0.16 0.12 0.1015 yrs 1.08 1 0.89 0.69 0.54 0.39 0.28 0.18 0.13 0.1125 yrs 1.22 1.12 1 0.77 0.61 0.44 0.32 0.20 0.15 0.1235 yrs 1.57 1.45 1.29 1 0.79 0.57 0.41 0.26 0.19 0.1645 yrs 2.00 1.85 1.64 1.27 1 0.73 0.52 0.33 0.24 0.2055 yrs 2.75 2.54 2.26 1.75 1.38 1 0.72 0.45 0.34 0.2865 yrs 3.84 3.55 3.15 2.44 1.92 1.40 1 0.63 0.47 0.3875 yrs 6.08 5.61 4.99 3.87 3.04 2.21 1.58 1 0.74 0.6185 yrs 8.21 7.58 6.74 5.22 4.10 2.98 2.14 1.35 1 0.8295 yrs 9.99 9.22 8.20 6.35 4.99 3.63 2.60 1.64 1.22 1

a Age-related decreases in pupil area82 and crystalline lens transmission81 causean age-related decrease in circadian photoreception in phakic individuals. Circadianperformance for an age in the top row is shown relative to that of an age in the leftcolumn. To determine the relative circadian photoreception for undilated persons ofdifferent ages, select a reference age from the top row and compare it to ages in theleft column. For example, a 45 year old has roughly half the circadian photorecep-tion of a 10 year old and 3 times that of a 75 year old. To determine the relativeillumination needed by individuals of different ages to achieve equivalent circadianphotoreception, select an age from the left column and compare it to an age in thetop row. For example, a 45 year old needs roughly twice the illumination of a 10 yearold and a third of that of a 75 year old.11


thresholds for white light exceed typical residential light levels (cf.,Fig. 2) in unrestrained, undilated humans.10 Young adult subjects(w25 years old) free-run when lighting is less than 80 lux93 or200 lux.94 Astronauts (ages 37–46) free-run at typical space shuttleilluminances below 80 lux, producing circadian disruption, sleepimpairment and reduced neurobehavioral performance.64 Adultsunder 35 years old do not suppress melatonin when exposed to200 lux for 3 h.95 How much additional illuminance would havebeen required to exceed threshold and produce the photoentrain-ment or melatonin suppression studied in these experiments isunknown. Under these experimental conditions 80–200 lux wereinsufficient for pRGC photoreception in healthy sighted 25–35 yearold subjects. Significantly higher illuminances would also beinadequate for older adults with their decreased crystalline lenstransmittance and pupil area. For example, 128–320, 184–460,256–640, 400–1000, 536–1340, and 656–1640 lux would beinsufficient in 45, 55, 65, 75, 85 and 95 year old adults, respectively(cf., Table 1).11 These illuminances are much higher than averageresidential light levels as shown in Fig. 2.10,53

Optimal neurobiologic function depends on exposures to sunlight

Midwinter insomnia is common at high latitudes, affecting 80%of some populations.96,97 Extended bed rest studies (subjects 25–51years old) in windowless rooms result in progressive sleep deteri-oration, free-running rhythms, and dampening of circadianamplitudes, even with brighter-than-average daytime illuminanceof 200–500 lux.27 Sighted individuals with minimal sunlightexposure may experience insomnia, free-running rhythms, flat-tened hormonal profiles, cognitive difficulties and undetectablenocturnal melatonin levels which subsequently normalize withrestoration of normal sunlight exposure.98,99

Daily illumination and depressed mood are inversely corre-lated.100 Over 90% of people experience mood reductions duringperiods of overcast weather or seasonal reductions in length orintensity of daylight.101–103 Seasonal affective disorder (SAD) is onedebilitating extreme in a continuum of sunlight-deficiency-inducedneuropsychological disorders. SAD causes distress in up to 10% of



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general populations with higher incidences in women. The sub-syndromal yet clinically significant milder form of SAD causesdifficulty in an additional 20% of people.104 Interior residential andindustrial lighting does not change in brightness daily or season-ally, suggesting that artificial lighting is often inadequate forneurobiological needs and that most people require intermittentsunlight exposures at illuminances typically much higher than1000–3000 lux for optimal well-being (cf., Fig. 2). Nonseasonaldepression is also inversely correlated with average illumi-nance.105,106 The elderly have higher incidences of nonseasonal-type depression positively correlated with age.100,107,108

Exposure to sunlight is usually minimal and declines with aging

Young adults in industrialized countries typically receive only20–120 min of daily light exceeding 1000 lux.56,105,109,110 Elderlyadults receive only 1/3–2/3 as much daily bright light expo-sures.56,111 Additionally, older women average ½ to ¼ of the lightexposures as age-matched men.111,112 These lifestyle preferences forreduced light exposure in older adults occur when they insteadshould progressively increase ambient lighting by at least: 2, 3, 4, 6,8 and 10-fold by ages 45, 55, 65, 75, 85 and 95, respectively, tomaintain the circadian photoreception of their youth (cf., Table 1).11

Alzheimer’s patients receive less light than age-matchedcontrols.111 Once institutionalized they may receive fewer than10 min of daily light exceeding 1000 lux, with median ambient lightlevels as low as 54 lux.113,114

Morbidity associated with chronic circadian disruption

Shift work: circadian disruption, depressed melatonin and increasedmorbidity

People with normally entrained diurnal rhythms receivea nightly surge of melatonin. The duration of nocturnal melatoninsecretion parallels the length of the daily dark period which variesseasonally at higher latitudes. Melatonin’s anti-gonadal propertiesreduce fertility during certain months mediating optimal birthtiming for seasonal breeding animals.30 Prior to the 1930s, beforeelectric lighting became routine, human conception was seasonaland correlated with photoperiod at higher latitudes.115 Melatoninhas also been reported to possess oncostatic properties.48,116,117

Oncostatic and anti-gonadal effects may help explain the protec-tion offered by optimal nocturnal melatonin levels against theincidence and mortality of various cancers, particularly hormonal-dependent malignancies such as breast or prostate cancer.30,53

Up to 20% of industrialized employees work at night exposingthemselves to light that could potentially suppress normalnocturnal melatonin secretion if exposures are sufficient to do so.53

The ‘‘melatonin hypothesis’’ postulates that ‘‘light-at-night’’ (LAN)is an important factor in explaining the higher cancer risks found inindustrialized countries.53,118 Light suppression of nocturnalmelatonin probably does contribute to this higher cancer incidenceespecially in younger night workers exposed to bright lighting suchas that found in operating rooms, intensive care units and industrialapplications (cf., Fig. 2). The prevalence and degree of nocturnalmelatonin suppression during a nightshift depends critically on thespectrum, intensity, duration, and timing of light exposures.53 Alsoimportant is retinal illumination which varies among individuals,with age and lens status (cf., Table 1).11,119

Nightshift workers have been shown to receive less daily brightlight (>1000 lux) at less optimal times than dayshift workers.53,120

SCN function is enhanced with bright properly timed light expo-sures, deficiency of which may lead to pacemaker dysfunction.23,33

Perhaps most importantly, the majority of nightshift workersappear to maintain entrainments typical of day-active people


thereby being awake and working 4–5 nights per week during theirbiologic night.120 Chronodisruption itself is known to significantlyflatten melatonin amplitudes27 reflecting the dampened rhythmsof the underlying SCN which controls its pineal secretion. Theflattened melatonin amplitudes generally associated with rotatingshift work are therefore potentially largely attributable to theirchronic desynchrony and bright light deficiency rather than justnocturnal suppression of melatonin. Supporting underlyingSCN dysfunction as a source of the morbidity of shift workers istheir higher incidences of numerous diverse signs and symptomstypical of circadian dysfunction53,121–123 including insomnia,depression,124 elevated cortisol levels, cognitive impairmentwith hippocampal atrophy,23,122,123 metabolic disorders, increasedcardiovascular disease121 and premature mortality.125

Visual loss: circadian disruption, reduced cancer risk but earlymortality

Blind women have half the incidence of breast cancer as sightedcohorts suggesting their deficient photoreception protects theirdaily melatonin secretion from light suppression.53,126 Indeed, theincidence of most types of cancers in blindness is half that ofsighted people of either gender,127 a relationship that also holds forvisual loss.128 In a cohort of over 17,000 persons followed for 20years, the incidence of breast and prostate cancer was directlycorrelated with visual acuity.128 Remarkably, however, numerousinvestigators report that overall life expectancy of totally blindpersons or those with varying degrees of visual loss is significantlyreduced compared to sighted controls even after controlling forother risk factors.71–75,129 This reduced life expectancy is surprisingbecause relative immunity from cancer presumably should extendsurvival. There has been no compelling explanation to date for theassociation of vision loss with premature mortality, which has beendescribed as not explained ‘‘by potential confounders’’74 or ‘‘bytraditional risk factors for mortality’’.71

Most totally blind individuals experience abnormal circadianrhythms.34,65 Visual impairment may also reduce light exposure andrestrict outdoor activities resulting in pRGC light deficiency despiteviable photoreceptors that might otherwise provide effective photo-entrainment and SCN function.100 The insomnia of blindness69 andvisual loss130 produces a nearly 3-fold increased prevalence of shortsleep syndrome (sleeping 5 or less hours nightly) in comparison tosighted controls.131 Sleep loss is a risk factor for metabolic andcardiovascular disease.15 Blind subjects are predisposed to metabolic,cardiovascular and memory deficits which have been attributed totheir overall elevations of adrenocorticotropin hormone (ACTH) andcortisol, flattened rhythms with loss of the important early night nadirof these hormones, and sleep fragmentation with deficient slow wavesleep activity.76 All of these are signs of SCN dampening which mayinitiate a chain of adverse sequelae.15,16,18,132–142

Chronic circadian disruption may lead to suboptimal internalsynchronization of physiological processes that could interferewith each other if not properly timed29 and consequently inducebiological stress. The stress response may or may not activate thetwo functionally interrelated and reciprocally innervated pathwaysof the stress cascade, the hypothalamic–pituitary–adrenal (HPA)axis and the sympathetic nervous system (SNS).143 HPA axisglucocorticoids and SNS catecholamines mediate morbidity asso-ciated with chronic activation of the stress cascade. SCN set thedaily rhythm and amplitude of cortisol by maintaining simulta-neous excitatory and inhibitory connections within the HPA axisresponsible for glucocorticoid production.15,18 SCN normallyrestrain the HPA axis and check excessive stress responses, but thisinhibition may be lost if its efferent signals are dampened.15,18



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We hypothesize that the increased risks of morbidity and earlymortality associated with visual loss and blindness may be due tothe many consequences of chronic chronodisruption with reduc-tion of SCN output amplitudes, metabolic imbalances and anunchecked activation of the stress cascade. This may lead to chronichypercortisolemia, as well as dampening of hormonal and physi-ological rhythms and peripheral cell asynchrony. Sighted non-shiftworking individuals have the same potential risks if bright lightexposures are insufficient or ocular aging predisposes them to lightdeficiency.11,27,64,83,98,99,142

Light deficiency may contribute to common age-relatedmorbidities

By 45 years of age circadian photoreception has alreadydecreased by 50% (cf., Table 1) which combined with typicalpatterns of reduced bright light exposure105,109 may explain whysignificantly reduced melatonin amplitudes have been found by thefourth decade in some individuals.144 Bright light exposure hasbeen shown to increase nocturnal melatonin amplitudes in bothyoung and elderly adults, restoring them to youthful levels in theolder patients.56 Higher melatonin levels are associated withfitness51 and levels are found to be relatively preserved in healthymedically screened elderly.44 Conversely, low melatonin ampli-tudes are correlated with diverse diseases.45–49 Prospective studiesnested within the Harvard Nurses Study have shown that highernocturnal melatonin amplitudes were associated with a lowerincidence of breast cancer over four year follow-up periods for bothpre and postmenopausal women.48,145

Herljevic et al.119 compared nocturnal melatonin suppression bymonochromatic blue (456 nm) light in two groups of women withmean ages of 24 and 57 years. Older women were insensitive toblue light sufficiently intense to significantly suppress melatonin inyouthful women. This study demonstrates that age-related crys-talline lens yellowing reduced ocular transmission of the bluewavelengths optimal for circadian photoreception to levels inef-fective for nonvisual photoreception, even under the best ofcircumstances (dilated pupils, light source-directed gaze fixationand optimal monochromatic wavelength). The younger womenmoreover produced twice the total daily melatonin as the olderwomen. A similar experimental protocol in younger (mean age, 23years) and older (mean age, 66 years) men also demonstrated bluelight suppression by the crystalline lenses of the older groupreducing otherwise significantly enhanced short-wavelength-light-induced responses to subjective alertness, sleepiness and mood.79

Unfortunately environmental light exposures appear to declinewith advancing age56,111 just as pupillary miosis and crystalline lensyellowing block more of the blue light optimal for circadianphotoreception.11 This decreasing bright light occurs at ages whenolder people should instead be increasing their ambient illumina-tion by factors ranging from 2 to 10 fold to simply maintain theequivalent circadian photoreception of their youth (Table 1).11

Melatonin is considered the most accurate marker of human SCNfunction because the timing of its plasma rhythm30 and amplitude31

is directly orchestrated by the circadian pacemaker.32 Humanmelatonin levels decline with light deficiency, flattening progres-sively as bright light deficiency persists over days,27 and falling by asmuch as 33% after only four days of near darkness.146 Melatoninlevels may become undetectable with protracted light insuffi-ciency.98 These and other studies suggest that light deficiency isdetrimental to SCN function even in young people and, as will bediscussed below, that bright environmental light may restoreeffective underlying pacemaker function even in elderly subjects.

Light intensities of at least several thousand lux can compensatefor age-related reductions in retinal illumination,11 so elderly adults


with intact pRGCs who spend ample time outdoors should receivesufficient illumination for circadian demands (cf., Fig. 2). Environ-mental light exposures have not been monitored in studies exam-ining whether melatonin levels decline with aging. Varying lighthistories may explain conflicting reports of possible declines innocturnal melatonin production. Lifestyles of healthy elderlyretaining youthful melatonin levels likely include regular exposuresto bright environmental light.44,51

Light deficiency as a possible cause of chronodisruption

Light is the primary zeitgeber in humans.33,34 Illuminance andphotoperiod are key environmental factors influencing human SCNfunction.24 The strength (amplitude) of SCN rhythmic signals areinfluenced by bright light exposure, deficiency of which may initiatean interlocking cascade of events potentially causing loss of physicaland psychological well-being.15,16,18,132–142 With insufficient lightexposure, hormonal and physiological amplitudes may bereduced.23,27,98 One dampened rhythm is associated with others,reflecting their common origins in weakened SCN control22,27,76,98,147

that may increase the risk of all-cause morbidity.25 We thereforesuggest that pRGC light deficiency maycontribute to chronodisruptionin some individuals, even if light exposures are otherwise properlytimed, and that this risk increases substantially with age in phakic(native crystalline lens in place within the eye) subjects due to ocularsenescence which reduces retinal illuminance for pRGC photorecep-tion.11,83 Restoring bright properly timed light exposures sufficient tocompensate for possible age-related crystalline lens yellowing andpupillary miosis improves SCN function as measured by restoredhormonal levels and core body temperature amplitudes.56,98,99

Bright light’s effects on human disease, physiology and function

This section examines some of the proven nonvisual effects ofbright light, describing how morbidity from light deficiency may bereversible with restoration of effective environmental illuminance.

InsomniaInsomnia in elderly people may be aggravated by low ambient

illumination levels.56,114 Bright daytime light consolidates fragmentedinto continuous sleep patterns fortifying circadian rhythms.148

Threshold intensities of at least 2500–3000 lux have been shown toreduce or alleviate insomnia56,149,150; increase sleep efficiency, totalsleep time, and restorative slow wave sleep151; and improve daytimevigilance and sleepiness.149 Light therapy for insomnia is also effectivefor the institutionalized elderly.152,153 Cataract surgery alone withcolorless ultraviolet (UV)-only blocking IOLs has been shown toreduce the incidence of insomnia by 50%,130,154 without alteringhabitual light exposures. Reduced circadian photoreception due tocrystalline lens yellowing and pupillary miosis becomes significant byearly middle age. Cataract surgery can restore the youthfulness ofcircadian photoreception by up to 4 decades when colorless UV-onlyblocking IOLs are utilized.11,79,119

The mechanisms by which bright daytime light improvesnighttime sleep quality have yet to be determined, but light is theparamount zeitgeber33 and enhanced SCN sleep/wake signalgeneration may be involved.21,150 Light may modulate sym-pathoexcitation.62 Bright evening light alters sympathovagalbalance, decreasing sympathetic activation which might otherwiseprevent deeper and slow wave sleep.155,155a Light-inducedincreases in central nervous system (CNS) serotonin17 may facilitatesleep by stimulating serotonergic brain centers such as the raphenuclei implicated in the promotion of slow wave sleep.156 Sleep andparticularly slow wave sleep have been proposed to inhibit the HPAaxis and cortisol secretion.76,157



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Subjective mood and well-beingBright light significantly improves subjective mood,100 well-

being, optimism, quality of life and social function in general60 andelderly158 populations free of depression. Employees experienceimproved vitality and reduced depressive mood with increasedworkplace illumination.59,60

Lambert et al.17 sampled internal jugular vein blood to determineCNS neurotransmitter concentrations under different light expo-sures. Brain serotonin (5-HT) production rate varied immediately anddirectly with prevailing brightness and duration of sunlight.17 Sero-tonin levels also increase with light therapy for nonseasonaldepression,159 suggesting that serotonin contributes to the stronglypositive effect of bright light on mood. Serotonin stimulates neuro-genesis and activates the 5-HT1A receptors160 responsible forreducing anxiety, depression and increasing feelings of well-being.161

DepressionMorning light therapy for seasonal (SAD and sub-syndromal

variants) depression with 2 h of 2500 lux or 30 min of 10,000 luxlight-box illumination provides 70% response rates compared to nolight intervention.104 Meta-analyses confirm that bright light therapyis effective for treating both seasonal and nonseasonal depression andthat shorter (bluer) wavelengths are more effective than longer(redder) ones.57,58,162 Beyond improving depression, light treatmentincreases circadian amplitude of core body temperature, enhancesenergy and improves sleep in nonseasonal major depression,163

corroborating suggestions that SCN dysfunction contributes todepression and its circadian control is enhanced by bright light.23,33

Melatonin amplitudesBright daytime light (�2500 lux) increases nocturnal melatonin

amplitudes in young164–166 and restores youthful levels in olderadults.56,167 Elderly insomniacs produce less nocturnal melatoninand receive less environmental light than controls withoutinsomnia.56 Light therapy with 2500 lux for 2 h twice daily restoresmelatonin amplitudes and reduces insomnia in elderly patients.56

Sighted individuals restricted to prolonged indoor lighting such asextended convalescences or choosing minimal bright light expo-sure lifestyles may experience circadian disruption includingdampening of normal hormonal amplitudes and sleep distur-bance.27,98 Undetectable melatonin levels may normalize withrestoration of adequate light and sleep disturbances resolve.98

CognitionBright light immediately enhances cognitive performance

depending on its intensity and spectrum. Cognition for complextasks significantly improves with blue (w470 nm) as compared tomonochromatic green (w550 nm) light.9 Sunlight is much brighterthan typical indoor lighting and has an optimal spectrum rich inblue wavelengths. Student performance in sunlit classrooms is5–14% better than test scores under artificial lighting.168 Daylitworkplaces significantly increase office productivity169 whereaswindowless settings reduce jobsite productivity and increaseabsenteeism.170 Workplace lighting rich in blue wavelengthsreduces fatigue and daytime sleepiness while increasing alertness,performance and accuracy.59 Cognition of Alzheimer patientsimproves with bright light exposures.152,171 This effect may in partbe mediated by light-induced improvements of sleep – hippo-campal function in elderly people which have been shown to bevery sensitive even to mildly disrupted sleep.172 These studiessuggest that blue light blocking by the aged crystalline lens79,119

may contribute to age-related cognitive declines and that cataractsurgery with IOLs transmitting blue light may be helpful inimproving cognition. Cataract surgery with colorless UV-onlyblocking intraocular lenses reduces daytime sleepiness.154


Alzheimer’s diseaseAlzheimer’s disease disrupts sleep–wake and other biological

rhythms. Melatonin amplitudes are typically low and correlatedwith disease severity.46 Sleep–wake rhythms become increasinglydisturbed with disease progression.46,113 Nursing home lighting istypically poor114 and circadian rhythm abnormalities includingfree-running46,173 may occur in up to 97% of residents.174 Nineteennursing home residents were each objectively monitored for oneday and found to display both sleep and wakefulness during each ofthe 24 h.175 Dampened SCN rhythms may prevent consolidatedalterations of active alerting for wakefulness and active sleeppromotion during their respective circadian phases.21,174,176 If visionis intact,23 restoring bright daytime light (�2500 lux) can improvecognition and nocturnal sleep, and reduce daytime napping andagitation171,177 except in the most advanced stages of Alzheimer’sdisease. Artificial dawn-studies indicate that not only the level ofdaytime light exposure, but also the presence of a clear daily dark–light transition signal may be important to support SCN function.178

A diagnosis of Alzheimer’s disease is sometimes considereda contraindication for cataract surgery thus placing this largelyindoor-dwelling population174 in greater jeopardy of pRGC lightdeficiency. Modern cataract surgery using topical or local anes-thesia requires patient cooperation which could be problematic indemented patients. General anesthesia for cataract extraction isnow uncommon but used occasionally when necessary. Patients inthe earliest stages of dementia and Alzheimer’s disease may benefitfrom an ophthalmic evaluation while their cooperation is stillpossible. Cataract surgery, in at least one eye if indicated, canimprove circadian photoreception and possibly reduce the adverseeffect of chronodisruption in these patients.11

Therapeutic intervention

Cataract surgery

Cataract surgery removes a barrier to short wavelength lightoptimal for circadian photoreception. The yellowed crystalline lensis surgically replaced with an intraocular lens (IOL). UV-onlyblocking IOLs are the current standard of care in ophthalmology.They absorb most UV radiation and possibly some additional violetlight, but they maximally transmit blue light.7,179 Asplund andLindblad demonstrated that cataract surgery with UV-blocking IOLssignificantly improves nocturnal sleep and reduces daytimesleepiness.130,154 These benefits increase with second eye surgeryand over a 9 month follow-up. Anticipated prevalence of poor sleepwas reduced by 50% without altering habitual light exposurepatterns.130,154

In the early 1990’s yellowish blue-blocking IOLs were designedwith the expectation that they might improve photopic vision andlater promoted to reduce the hypothetical risk of age-relatedmacular degeneration (AMD). These conjectured benefits havenever been proven clinically.180 Blue-blocking IOLs occlude mostUV radiation which is potentially harmful and not useful for vision.They also eliminate substantial amounts of violet light and the bluelight which is optimal for pRGC photoreception. Blue blocking IOLsare still in use today.180

Evidence documenting the vital role of blue light for optimalsystemic and mental health has grown rapidly. Cataract pop-ulations potentially have the most to benefit from optimal pRGCphotoreception because they typically have less daily light expo-sure than younger adults, smaller pupils, and higher prevalencesof insomnia, depression and cognitive difficulty.11 IOLs that maxi-mally transmit blue light may potentially help compensate forsuboptimal environmental light exposures and potential pRGCpopulation losses due to aging or disease.7,11,79,119


Practice points

1) Nonvisual light deficiency cannot be perceived consciously.Typical residential illuminance is too low for circadian needseven in young adults. Properly timed exposure to sunlight orother bright light sources is vital for mental and physicalwell-being in all age groups.11 Optimal intensity and timingof environmental light exposure depend on many indi-vidual-specific variables including length of the endogenouscircadian period, lens transmittance, pupillary diameter,integrity of pRGC photoreceptor populations and prior lighthistory. In general, several hours of at least 2500 lux of blue-weighted light exposure (ideally sunlight) starting early inthe morning benefit most people. Bright light immediatelyanddirectlyenhancescognition,alertness,performanceandmood, so bright environments throughout the day provideadditional benefits, especially for middle-aged or olderadults.

2) Progressive, age-related losses in circadian photore-ception potentially occur in everyone, regardless of theirvisual acuity.11 It may be possible to maintain youthfulcircadian photoreception with adequate daily outdoordaylight exposure or by using adequately bright andproperly timed indoor lighting to compensate for age-related losses in pupillary area, crystalline lens trans-mittance and perhaps pRGC populations.11

3) Bright, properly timed light exposures are helpful formanaging symptoms of circadian dysfunction includinginsomnia, depression, reduced cognitive function andfatigue. These exposures may help normalize signs ofchronodisruption including depressed hormonal ampli-tudes, increased ACTH, CRH or cortisol levels, and loss ofnormal daily core body temperature rhythms.

4) Evolution is probably responsible for the fact that skylight’sspectrum and intensity are optimal for pRGC photorecep-tion. Normal environmental light exposure180,184 andcataract surgery181 do not increase the risk of age-relatedmacular degeneration. Direct sun gazing is hazardous,especially near midday.183,184 Solar UV-B radiation(280–320 nm) is a risk factor for cataractogenesis.186 Phakicchildren and adults should wear a brimmed hat andUV-protective lenses in bright outdoor environments nearmidday.179,183,185


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Phototoxicity

The retinal phototoxicity-AMD hypothesis posits that AMDresults in part from cumulative retinal damage due to repetitiveacute retinal phototoxicity (photic retinopathy) caused by envi-ronmental light exposure.7,180 This hypothesis remains unprovenafter decades of careful study. The vast majority (10/12) of the largemajor epidemiological investigations found no correlation betweenAMD and environmental light exposure.180 They should haveprovided convincing evidence if a significant correlation did exist.Their failure to do so may be due to an otherwise weak correlationbeing confounded by variability in lifestyle choices, geneticsusceptibility or diet.7 Cataract surgery markedly increases retinalilluminance from environmental light, as shown in Fig. 3, identi-fying another critical weakness of the AMD-phototoxicity hypoth-esis: large prospective trials demonstrate conclusively that cataractsurgery does not increase the progression of AMD.181 Long-termfollow-up of SAD patients treated with 10,000 lux light box therapyreveal no ocular abnormalities.182 Taken together the weight ofclinical evidence indicates that normal environmental light expo-sure does not pose a retinal hazard for phakic or pseudophakic(cataract surgery with an artificial lens implanted) adults. Phakicindividuals are at risk of cataractogenesis from solar UV-B radiation,so brimmed hats and UV-protective sunglasses are advisable whenthey are outdoors near midday in bright sunny environ-ments.179,183–185 Habitual or fashion use of sunglasses may becounterproductive for nonvisual photoreception and good healthin most people when used outside the brightest midday period(11:00 to 15:00 h), unless the landscape is highly reflective.183

Architectural lighting and public education

Modern Illumination engineering has produced a growing rangeof energy efficient light sources with luminance spectra closer tonatural outdoor lighting than conventional incandescent sources.This work continues with emphasis on higher luminances andenvironmentally friendlier components. There is still a need toupdate existing work place and residential lighting to provide thehigher illuminances that older adults need to achieve more youthfulcircadian photoreception. Residential lighting could be optimized bytime-structured illuminance designed for circadian demands duringdaytime hours and limited to lower thresholds required forconscious vision during the geophysical night. Architectural trendsalready support this concept with the use of skylights, largewindows, passive light pipe illuminators, and temperature-controlled solaria that are especially valuable for retirement livingand extended care facilities. Medical and public education programsdisseminating information regarding the inadequacies of exclusivereliance on residential levels of artificial lighting, importance ofavoiding light-at-night and potential benefits of properly timedbright, ideally natural, light exposures may also reduce morbidity.

Conclusions

Environmental illumination plays an important role in humanhealth. The eye mediates this effect because retinal ganglion photore-ceptors provide vital information about ambient illumination andlight–dark cycles to nonvisual (non-image-forming) brain centersincluding the SCN. These data are necessary to coordinate metabolichomeostasis thus avoiding physiological stress and assure optimallevels and proper timing of the synthesis of essential CNS hormonesand neurotransmitters including cortisol, melatonin and serotonin. SCNcontrol timing and coordination of numerous central and peripheralphysiological processes, but require bright, properly timed environ-mental light exposures for robust circadian amplitudes, optimal


neuropsychological functioning and photoentrainment of their typi-cally non-24 h periodicity to match geophysical day–night cycles.

Ocular aging and inadequate environmental illumination limitnonvisual photoreception. Common morbidities often assumed to beage-related inevitabilities may result in part from light-deficiency-induced SCN signal output dampening that may produce chro-nodisruption and possible hyperactivation of the HPA axis and stresscascade. Chronic chronodisruption may increase the risks ofinsomnia, depression, cognitive impairment, dementia, inflamma-tion, obesity, metabolic syndrome, cardiovascular disease andpremature mortality. Interactions are complex, but light deficiencymay be a common causative factor. We suggest that chronic SCNdysfunction could account for the strong association of blindness andvisual loss with early mortality. Sighted, non-shift working individ-uals may also be at risk for chronodisruption from pRGC light defi-ciency even if light exposures are otherwise properly timed. Theserisks would increase with aging due to progressive loss of retinalillumination caused by decreasing pupillary area and crystalline lenstransmission. Morbidity may be decreased and quality of lifeimproved by (1) lifestyle changes that increase sunlight exposure, (2)light supplementation and natural lighting in homes and buildings,(3) cataract surgery, and (4) exogenous melatonin entrainment fortotally blind individuals lacking pRGC photoreception.


Research agenda

Future research should address the following issues.

1) The effect of cataract extraction on nonvisual photore-ception requires further investigation. Nocturnal mela-tonin suppression and other nonvisual effects could becompared in aged-matched phakic and pseudophakicsubjects. Alternatively patients could serve as their owncontrols after cataract surgery has been performed inthe first eye if monocular light exposures were utilizedand melatonin suppression were compared in thepseudophakic versus phakic eye (recognizing that thepercentage of melatonin suppression from monocularlight exposure may be less than bilateral ones).187

Additional objective parameters that could providefurther insight into the effect of cataract surgery oncircadian photoreception include body temperature,cortisol, melatonin, markers of inflammation, glucosemetabolism, lipids, blood pressure, objective sleepquality and cognitive function. Environmental lightexposure, pupil diameter, and IOL transmission shouldbe carefully controlled, as well as other parameterspotentially affecting clinical outcomes such as patients’medications, diet, pupillary area, IOL type, dietarysupplementation, smoking, alcohol consumption, shiftwork, recent multi-time zone travel, daily time outdoors,season of testing, geographical latitude, and measuredenvironmental light exposure. Potential differencesbetween UV- and blue-blocking IOLs should be exploredespecially with regards to cognitive performance,insomnia and subjective mood.

2) Alzheimer’s disease patients should be studied to see ifpseudophakia affects the incidence, severity andprogression of their disease and its frequently comorbidsleep–wake disturbances.

3) Noninvasive, convenient, cost effective methods fortesting pRGC function and viability would be extremelyuseful. These tests would be valuable in determining ifpRGC function itself declines with aging and whetherlosses are affected by different systemic or oculardiseases.

4) People with visual impairment have early mortality.Chronodisruption in visually blind people may improvewith exogenous melatonin, but this therapy may besuboptimal and/or unnecessary for individuals withintact pRGC photoreception. Visually impaired patientswith intact pRGC photoreception should be monitoredfor laboratory evidence of chronodisruption and todetermine if these parameters improve with effectiveenvironmental light exposure.

5) Research caveats: Optimal human sensitivity for mela-tonin suppression was not determined until 20015 andpRGCs were not identified until 2002.1,188 Prior to thesediscoveries traditional rod and/or cone photoreceptorswere assumed to mediate all photic effects. The phot-opic ‘‘lux’’ is the most widely used unit for quantifyingilluminance. This unit is a photometric term character-izing how effectively a light exposure elicits cone-mediated (bright light) vision. A scotopic lux is alsodefined for rod-mediated (dim light) vision but there isno international standard ‘‘circadian lux’’ unit for accu-rately characterizing a light source’s nonvisual pRGCspectral (luminous) efficiency. Care should be taken incomparing broad spectrum and monochromatic wave-length results until a standardized circadian lux unit hasbeen adopted. Many circadian studies fail to (1) performor describe ophthalmic screening of test subjects or (2)control for critical parameters such as lens transmissionand pupillary area. Some investigations exclude

subjects with cataract but then consider phakic andpseudophakic patients to be equivalent despite themarkedly increased retinal illuminances provided byIOLs. Studies on ‘‘blind’’ subjects typically fail to specifytheir definition of blindness. Therefore, subjects mightbe ‘‘legally blind’’ (markedly impaired visual acuity orvisual field in both eyes), ‘‘visually blind’’ (no consciouslight perception but with intact pRGC photoreception) or‘‘totally blind’’ (no visual or nonvisual photoreception).Pharmacological pupillary dilation increases retinalillumination and therefore circadian efficiency signifi-cantly.92 Additionally, the use of chin rests with lightsource-directed fixation91 during exposures produceresults that markedly overestimates light efficiency andunderestimates light requirements for circadian effectsin normal environmental exposures. Study protocolsvary widely and many fail to specify fundamental lightexposure parameters such as the spectrum of the lightsource used. Finally, there are critical differences amongspecies in circadian sensitivity making extrapolation ofexperimental animal data to clinical circumstanceshighly problematic. For example, nocturnal rodents maybe 1000 to 10,000 times more sensitive to light thandiurnal humans, and their peak spectral sensitivity(w480 nm) is roughly 20 nm longer (redder) than that ofhumans (460 nm).10,189,190


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Conflict of interest statement

The authors have no proprietary interests in any manufacturersor products. The authors received no funding for this research. Dr.Turner and Dr. Van Someren have no personal competing interests.Dr. Mainster is a consultant for Abbott Medical Optics, Iridex andOcular Instruments Corporations.

References

1. Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cellsthat set the circadian clock. Science 2002;295:1070–3.

2. Hannibal J, Fahrenkrug J. Neuronal input pathways to the brain’s biologicalclock and their functional significance. Adv Anat Embryol Cell Biol2006;182:1–71.

3. Berson DM. Strange vision: ganglion cells as circadian photoreceptors.Trends Neurosci 2003;26:314–20.

4. Thapan K, Arendt J, Skene DJ. An action spectrum for melatonin suppres-sion: evidence for a novel non-rod, non-cone photoreceptor system inhumans. J Physiol 2001;535:261–7.

5. Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, et al.Action spectrum for melatonin regulation in humans: evidence for a novelcircadian photoreceptor. J Neurosci 2001;21:6405–12.

6. Lockley SW, Evans EE, Scheer FA, Brainard GC, Czeisler CA, Aeschbach D.Short-wavelength sensitivity for the direct effects of light on alertness,vigilance, and the waking electroencephalogram in humans. Sleep2006;29:161–8.

7. Mainster MA. Violet and blue light blocking intraocular lenses: photo-protection versus photoreception. Br J Ophthalmol 2006;90:784–92.

8. Cajochen C, Munch M, Kobialka S, Krauchi K, Steiner R, Oelhafen P, et al.High sensitivity of human melatonin, alertness, thermoregulation, andheart rate to short wavelength light. J Clin Endocrinol Metab 2005;90:1311–6.

9. Vandewalle G, Gais S, Schabus M, Balteau E, Carrier J, Darsaud A, et al.Wavelength-Dependent Modulation of Brain Responses to a WorkingMemory Task by Daytime Light Exposure. Cereb Cortex 2007;17:2788–95.

10. Rea MS, Figueiro MG, Bullough JD, Bierman A. A model of photo-transduction by the human circadian system. Brain Res Brain Res Rev2005;50:213–28;

10a. Mure LS, Rieux C, Hattar S, Cooper HM. Melanopsin-dependent nonvisualresponses: evidence for photopigment bistability in vivo. J Biol Rhythms2007;22:411–24.

* The most important references are denoted by an asterisk.



ARTICLE IN PRESS

*11. Turner PL, Mainster MA. Circadian photoreception: Aging and the eye’simportant role in systemic health. Br J Ophthalmol 2008;92:1439–44.

12. Lubkin V, Beizai P, Sadun AA. The eye as metronome of the body. SurvOphthalmol 2002;47:17–26.

13. Gachon F, Nagoshi E, Brown SA, Ripperger J, Schibler U. The mammaliancircadian timing system: from gene expression to physiology. Chromosoma2004;113:103–12.

14. Czeisler CA, Klerman EB. Circadian and sleep-dependent regulation ofhormone release in humans. Recent Prog Horm Res 1999;54:97–130.discussion 130–132.

*15. Buijs RM, Scheer FA, Kreier F, Yi C, Bos N, Goncharuk VD, et al. Chapter 20:Organization of circadian functions: interaction with the body. Prog BrainRes 2006;153:341–60.

*16. Kalsbeek A, Ruiter M, La Fleur SE, Cailotto C, Kreier F, Buijs RM. Chapter 17:The hypothalamic clock and its control of glucose homeostasis. Prog BrainRes 2006;153:283–307.

17. Lambert GW, Reid C, Kaye DM, Jennings GL, Esler MD. Effect of sunlight andseason on serotonin turnover in the brain. Lancet 2002;360:1840–2.

*18. Lupien SJ, Nair NP, Briere S, Maheu F, Tu MT, Lemay M, et al. Increasedcortisol levels and impaired cognition in human aging: implication fordepression and dementia in later life. Rev Neurosci 1999;10:117–39.

19. Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW, et al.Stability, precision, and near-24-hour period of the human circadianpacemaker. Science 1999;284:2177–81.

20. Stratmann M, Schibler U. Properties, entrainment, and physiological func-tions of mammalian peripheral oscillators. J Biol Rhythms 2006;21:494–506.

21. Mistlberger RE. Circadian regulation of sleep in mammals: role of thesuprachiasmatic nucleus. Brain Res Brain Res Rev 2005;49:429–54.

22. Klerman EB. Clinical aspects of human circadian rhythms. J Biol Rhythms2005;20:375–86.

*23. Van Someren EJ, Riemersma RF, Swaab DF. Functional plasticity of thecircadian timing system in old age: light exposure. Prog Brain Res2002;138:205–31.

24. Hofman MA, Swaab DF. Living by the clock: the circadian pacemaker inolder people. Ageing Res Rev 2006;5:33–51.

25. Hastings MH, Reddy AB, Maywood ES. A clockwork web: circadian timingin brain and periphery, in health and disease. Nat Rev Neurosci2003;4:649–61.

26. Nagoshi E, Saini C, Bauer C, Laroche T, Naef F, Schibler U. Circadian geneexpression in individual fibroblasts: cell-autonomous and self-sustainedoscillators pass time to daughter cells. Cell 2004;119:693–705.

27. Monk TH, Buysse DJ, Billy BD, Kennedy KS, Kupfer DJ. The effects on humansleep and circadian rhythms of 17 days of continuous bedrest in theabsence of daylight. Sleep 1997;20:858–64.

28. Erren TC, Reiter RJ. A generalized theory of carcinogenesis due to chro-nodisruption. Neuro Endocrinol Lett 2008;29:815–21.

*29. Van Someren EJ, Riemersma-Van Der Lek RF. Live to the rhythm, slave tothe rhythm. Sleep Med Rev 2007;11:465–84.

*30. Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B,Hardeland R. Melatonin: Nature’s most versatile biological signal? Febs J2006;273:2813–38.

31. Perreau-Lenz S, Kalsbeek A, Garidou ML, Wortel J, van der Vliet J, vanHeijningen C, et al. Suprachiasmatic control of melatonin synthesis in rats:inhibitory and stimulatory mechanisms. Eur J Neurosci 2003;17:221–8.

32. St Hilaire MA, Gronfier C, Zeitzer JM, Klerman EB. A physiologically basedmathematical model of melatonin including ocular light suppression andinteractions with the circadian pacemaker. J Pineal Res 2007;43:294–304.

33. Czeisler CA. The effect of light on the human circadian pacemaker. CibaFound Symp 1995;183:254–90. discussion 290–302.

34. Skene DJ, Lockley SW, Thapan K, Arendt J. Effects of light on humancircadian rhythms. Reprod Nutr Dev 1999;39:295–304.

35. Brainard GC, Hanifin JP, Rollag MD, Greeson J, Byrne B, Glickman G, et al.Human melatonin regulation is not mediated by the three cone photopicvisual system. J Clin Endocrinol Metab 2001;86:433–6.

36. Hu K, Van Someren EJ, Shea SA, Scheer FA. Reduction of scale invariance ofactivity fluctuations with aging and Alzheimer’s disease: Involvement ofthe circadian pacemaker. Proc Natl Acad Sci U S A; 2009.

37. Harper DG, Stopa EG, Kuo-Leblanc V, McKee AC, Asayama K, Volicer L, et al.Dorsomedial SCN neuronal subpopulations subserve different functions inhuman dementia. Brain 2008;131:1609–17.

38. Carvalho-Bos SS, Riemersma-van der Lek RF, Waterhouse J, Reilly T, VanSomeren EJ. Strong association of the rest-activity rhythm with well-beingin demented elderly women. Am J Geriatr Psychiatry 2007;15:92–100.

39. Huang YL, Liu RY, Wang QS, Van Someren EJ, Xu H, Zhou JN. Age-associateddifference in circadian sleep-wake and rest-activity rhythms. Physiol Behav2002;76:597–603.

40. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, manyderivatives: A never-ending interaction of melatonin with reactive oxygenand nitrogen species? J Pineal Res 2007;42:28–42.

41. Benot S, Goberna R, Reiter RJ, Garcia-Maurino S, Osuna C, Guerrero JM.Physiological levels of melatonin contribute to the antioxidant capacity ofhuman serum. J Pineal Res 1999;27:59–64.

42. Waldhauser F, Weiszenbacher G, Tatzer E, Gisinger B, Waldhauser M,Schemper M, et al. Alterations in nocturnal serum melatonin levels inhumans with growth and aging. J Clin Endocrinol Metab 1988;66:648–52.


43. Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM. Human melatoninproduction decreases with age. J Pineal Res 1986;3:379–88.

44. Zeitzer JM, Daniels JE, Duffy JF, Klerman EB, Shanahan TL, Dijk DJ, et al. Doplasma melatonin concentrations decline with age? Am J Med1999;107:432–6.

45. Halberg F, Cornelissen G, Ulmer W, Blank M, Hrushesky W, Wood P, et al.Cancer chronomics III. Chronomics for cancer, aging, melatonin andexperimental therapeutics researchers. J Exp Ther Oncol 2006;6:73–84.

46. Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, Okawa M.Melatonin secretion rhythm disorders in patients with senile dementia ofAlzheimer’s type with disturbed sleep-waking. Biol Psychiatry1999;45:417–21.

47. Yaprak M, Altun A, Vardar A, Aktoz M, Ciftci S, Ozbay G. Decreasednocturnal synthesis of melatonin in patients with coronary artery disease.Int J Cardiol 2003;89:103–7.

48. Schernhammer ES, Hankinson SE. Urinary melatonin levels and breastcancer risk. J Natl Cancer Inst 2005;97:1084–7.

49. Robeva R, Kirilov G, Tomova A, Kumanov P. Melatonin-insulin interactionsin patients with metabolic syndrome. J Pineal Res 2008;44:52–6.

50. Ferrari E, Cravello L, Falvo F, Barili L, Solerte SB, Fioravanti M, et al.Neuroendocrine features in extreme longevity. Exp Gerontol 2007;43:88–94.

51. Korkushko OV, Khavinson V, Shatilo VB, Magdich LV, Labunets IF. Circadianrhythms of pineal gland melatonin-forming function in healthy elderlypeople. Adv Gerontol 2004;15:70–5.

52. Gallagher III FW, Beasley WH, Gohren CF. Green thunderstorms observed.Bulletin of the American Meteorological Society 1996;77:2889–97.

53. Figueiro MG, Rea MS, Bullough JD. Does architectural lighting contribute tobreast cancer? J Carcinog 2006;5:20.

54. Lynch HJ, Deng MH, Wurtman RJ. Indirect effects of light: ecological andethological considerations. Ann N Y Acad Sci 1985;453:231–41.

55. Lack LC, Wright HR. Shorter wavelength light is more effective for changingmelatonin phase. Chronobiol Int 2003;20:1179–81.

56. Mishima K, Okawa M, Shimizu T, Hishikawa Y. Diminished melatoninsecretion in the elderly caused by insufficient environmental illumination. JClin Endocrinol Metab 2001;86:129–34.

57. Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen FM, Suppes T,et al. The efficacy of light therapy in the treatment of mood disorders:a review and meta-analysis of the evidence. Am J Psychiatry 2005;162:656–62.

58. Lee TM, Chan CC, Paterson JG, Janzen HL, Blashko CA. Spectral properties ofphototherapy for seasonal affective disorder: a meta-analysis. Acta Psy-chiatr Scand 1997;96:117–21.

59. Mills PR, Tomkins SC, Schlangen LJ. The effect of high correlated colourtemperature office lighting on employee wellbeing and work performance.J Circadian Rhythms 2007;5:2.

60. Partonen T, Lonnqvist J. Bright light improves vitality and alleviates distressin healthy people. J Affect Disord 2000;57:55–61.

61. Meijer JH, Watanabe K, Schaap J, Albus H, Detari L. Light responsiveness ofthe suprachiasmatic nucleus: long-term multiunit and single-unit record-ings in freely moving rats. J Neurosci 1998;18:9078–87.

62. Mutoh T, Shibata S, Korf HW, Okamura H. Melatonin modulates the light-induced sympathoexcitation and vagal suppression with participation ofthe suprachiasmatic nucleus in mice. J Physiol 2003;547:317–32.

63. Lucassen PJ, Hofman MA, Swaab DF. Increased light intensity prevents theage related loss of vasopressin-expressing neurons in the rat supra-chiasmatic nucleus. Brain Res 1995;693:261–6.

64. Dijk DJ, Neri DF, Wyatt JK, Ronda JM, Riel E, Ritz-De Cecco A, et al. Sleep,performance, circadian rhythms, and light-dark cycles during twospace shuttle flights. Am J Physiol Regul Integr Comp Physiol 2001;281:R1647–64.

65. Lockley SW, Skene DJ, Arendt J, Tabandeh H, Bird AC, Defrance R. Rela-tionship between melatonin rhythms and visual loss in the blind. J ClinEndocrinol Metab 1997;82:3763–70.

66. Czeisler CA, Shanahan TL, Klerman EB, Martens H, Brotman DJ, Emens JS,et al. Suppression of melatonin secretion in some blind patients by expo-sure to bright light. N Engl J Med 1995;332:6–11.

67. Lockley SW, Skene DJ, Tabandeh H, Bird AC, Defrance R, Arendt J. Rela-tionship between napping and melatonin in the blind. J Biol Rhythms1997;12:16–25.

68. Miles LE, Raynal DM, Wilson MA. Blind man living in normal society hascircadian rhythms of 24.9 hours. Science 1977;198:421–3.

69. Lewy AJ, Emens JS, Lefler BJ, Yuhas K, Jackman AR. Melatonin entrains free-running blind people according to a physiological dose-response curve.Chronobiol Int 2005;22:1093–106.

70. Lewy AJ, Bauer VK, Hasler BP, Kendall AR, Pires ML, Sack RL. Capturing thecircadian rhythms of free-running blind people with 0.5 mg melatonin.Brain Res 2001;918:96–100.

71. Knudtson MD, Klein BE, Klein R. Age-related eye disease, visual impairment,and survival: the Beaver Dam Eye Study. Arch Ophthalmol 2006;124:243–9.

72. Lee DJ, Gomez-Marin O, Lam BL, Zheng DD. Glaucoma and survival: theNational Health Interview Survey 1986-1994. Ophthalmology 2003;110:1476–83.

73. McCarty CA, Nanjan MB, Taylor HR. Vision impairment predicts 5 yearmortality. Br J Ophthalmol 2001;85:322–6.



ARTICLE IN PRESS

74. West SK, Munoz B, Istre J, Rubin GS, Friedman SM, Fried LP, et al. Mixed lensopacities and subsequent mortality. Arch Ophthalmol 2000;118:393–7.

75. Foong AW, Fong CW, Wong TY, Saw SM, Heng D, Foster PJ. Visual acuity andmortality in a chinese population. The Tanjong Pagar Study. Ophthalmology2008;115:802–7.

76. Fischer S, Smolnik R, Herms M, Born J, Fehm HL. Melatonin acutelyimproves the neuroendocrine architecture of sleep in blind individuals. JClin Endocrinol Metab 2003;88:5315–20.

77. Van Someren EJ, Scherder EJ, Swaab DF. Transcutaneous electrical nervestimulation (TENS) improves circadian rhythm disturbances in Alzheimerdisease. Alzheimer Dis Assoc Disord 1998;12:114–8.

78. Scherder EJ, Van Someren EJ, Swaab DF. Transcutaneous electrical nervestimulation (TENS) improves the rest-activity rhythm in midstage Alz-heimer’s disease. Behav Brain Res 1999;101:105–7.

79. Sletten TL, Revell VL, Middleton B, Lederle KA, Skene DJ. Age-relatedchanges in acute and phase-advancing responses to monochromatic light. JBiol Rhythms 2009;24:73–84.

80. Scheer FA, Buijs RM. Light affects morning salivary cortisol in humans. J ClinEndocrinol Metab 1999;84:3395–8.

81. Barker FM, Brainard GC. The Direct Spectral Transmittance of the ExcisedHuman Lens as a Function of Age, (FDA 785345 0090 RA). Washington, DC.:U.S. Food and Drug Administration; 1991.

82. Yang Y, Thompson K, Burns SA. Pupil location under mesopic, photopic, andpharmacologically dilated conditions. Invest Ophthalmol Vis Sci 2002;43:2508–12.

83. Charman WN. Age, lens transmittance, and the possible effects of light onmelatonin suppression. Ophthalmic Physiol Opt 2003;23:181–7.

84. Harman A, Abrahams B, Moore S, Hoskins R. Neuronal density in the humanretinal ganglion cell layer from 16-77 years. Anat Rec 2000;260:124–31.

85. Curcio CA, Owsley C, Jackson GR. Spare the rods, save the cones in agingand age-related maculopathy. Invest Ophthalmol Vis Sci 2000;41:2015–8.

86. Li RS, Chen BY, Tay DK, Chan HH, Pu ML, So KF. Melanopsin-expressingretinal ganglion cells are more injury-resistant in a chronic ocular hyper-tension model. Invest Ophthalmol Vis Sci 2006;47:2951–8.

87. Knight JA, Thompson S, Raboud JM, Hoffman BR. Light and exercise andmelatonin production in women. Am J Epidemiol 2005;162:1114–22.

88. Lee H-C. Introduction to Color Imaging Science. Cambridge: CambridgeUniversity Press; 2005.

89. Pears A. Strategic Study of Household Energy and Greenhouse Issues. In:Australia E, editor. Australian Greenhouse Office; 1998. p. 61–3.

90. Ryer AD. The light measurement handbook. Newburyport, MA: InternationalLight, Inc.; 1997.

91. Dawson D, Campbell SS. Bright light treatment: are we keeping oursubjects in the dark? Sleep 1990;13:267–71.

92. Gaddy JR, Rollag MD, Brainard GC. Pupil size regulation of threshold oflight-induced melatonin suppression. J Clin Endocrinol Metab 1993;77:1398–401.

93. Gronfier C, Wright Jr KP, Kronauer RE, Czeisler CA. Entrainment of thehuman circadian pacemaker to longer-than-24-h days. Proc Natl Acad Sci US A 2007;104:9081–6.

94. Middleton B, Stone BM, Arendt J. Human circadian phase in 12:12 h, 200:<8 lux and 1000: <8 lux light-dark cycles, without scheduled sleep oractivity. Neurosci Lett 2002;329:41–4.

95. McIntyre IM, Norman TR, Burrows GD, Armstrong SM. Quantal melatoninsuppression by exposure to low intensity light in man. Life Sci1989;45:327–32.

96. Nilssen O, Lipton R, Brenn T, Hoyer G, Boiko E, Tkatchev A. Sleepingproblems at 78 degrees north: the Svalbard Study. Acta Psychiatr Scand1997;95:44–8.

97. Husby R, Lingjaerde O. Prevalence of reported sleeplessness in northernNorway in relation to sex, age and season. Acta Psychiatr Scand 1990;81:542–7.

98. Oren DA, Giesen HA, Wehr TA. Restoration of detectable melatonin afterentrainment to a 24-hour schedule in a ’free-running’ man. Psychoneur-oendocrinology 1997;22:39–52.

99. Bloch KE, Brack T, Wirz-Justice A. Transient short free running circadianrhythm in a case of aneurysm near the suprachiasmatic nuclei. J NeurolNeurosurg Psychiatry 2005;76:1178–80.

100. Jean-Louis G, Kripke D, Cohen C, Zizi F, Wolintz A. Associations of ambientillumination with mood: contribution of ophthalmic dysfunctions. PhysiolBehav 2005;84:479–87.

101. Spoont MR, Depue RA, Krauss SS. Dimensional measurement of seasonalvariation in mood and behavior. Psychiatry Res 1991;39:269–84.

102. Harmatz MG, Well AD, Overtree CE, Kawamura KY, Rosal M, Ockene IS.Seasonal variation of depression and other moods: a longitudinal approach.J Biol Rhythms 2000;15:344–50.

103. Dam H, Jakobsen K, Mellerup E. Prevalence of winter depression inDenmark. Acta Psychiatr Scand 1998;97:1–4.

104. Miller AL. Epidemiology, etiology, and natural treatment of seasonalaffective disorder. Altern Med Rev 2005;10:5–13.

105. Espiritu RC, Kripke DF, Ancoli-Israel S, Mowen MA, Mason WJ, Fell RL, et al.Low illumination experienced by San Diego adults: association withatypical depressive symptoms. Biol Psychiatry 1994;35:403–7.

106. Haynes PL, Ancoli-Israel S, McQuaid J. Illuminating the impact of habitualbehaviors in depression. Chronobiol Int 2005;22:279–97.


107. Otsuka K, Yamanaka G, Shinagawa M, Murakami S, Yamanaka T, Shibata K,et al. Chronomic community screening reveals about 31% depression, elevatedblood pressure and infradian vascular rhythm alteration. Biomed Pharmac-other 2004;58(Suppl. 1):S48–55.

108. Yaffe K, Edwards ER, Covinsky KE, Lui LY, Eng C. Depressive symptoms andrisk of mortality in frail, community-living elderly persons. Am J GeriatrPsychiatry 2003;11:561–7.

109. Savides TJ, Messin S, Senger C, Kripke DF. Natural light exposure of youngadults. Physiol Behav 1986;38:571–4.

110. Hebert M, Dumont M, Paquet J. Seasonal and diurnal patterns of humanillumination under natural conditions. Chronobiol Int 1998;15:59–70.

111. Campbell SS, Kripke DF, Gillin JC, Hrubovcak JC. Exposure to light in healthyelderly subjects and Alzheimer’s patients. Physiol Behav 1988;42:141–4.

112. Duncan DD, Munoz B, West SK. Assessment of ocular exposure to visiblelight for population studies. Dev Ophthalmol 2002;35:76–92.

113. Ancoli-Israel S, Klauber MR, Jones DW, Kripke DF, Martin J, Mason W, et al.Variations in circadian rhythms of activity, sleep, and light exposure relatedto dementia in nursing-home patients. Sleep 1997;20:18–23.

114. Shochat T, Martin J, Marler M, Ancoli-Israel S. Illumination levels in nursinghome patients: effects on sleep and activity rhythms. J Sleep Res 2000;9:373–9.

115. Roenneberg T, Aschoff J. Annual rhythm of human reproduction: II. Envi-ronmental correlations. J Biol Rhythms 1990;5:217–39.

116. Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: theneuroendocrine/circadian melatonin signal. Endocrine 2005;27:179–88.

117. Erren TC, Pape HG, Reiter RJ, Piekarski C. Chronodisruption and cancer.Naturwissenschaften 2008;95:367–82.

118. Stevens RG, Davis S. The melatonin hypothesis: electric power and breastcancer. Environ Health Perspect 1996;104(Suppl. 1):135–40.

*119. Herljevic M, Middleton B, Thapan K, Skene DJ. Light-induced melatoninsuppression: age-related reduction in response to short wavelength light.Exp Gerontol 2005;40:237–42.

120. Folkard S. Do permanent night workers show circadian adjustment? A reviewbased on the endogenous melatonin rhythm. Chronobiol Int 2008;25:215–24.

121. Knutsson A. Health disorders of shift workers. Occup Med (Lond) 2003;53:103–8.

122. Rouch I, Wild P, Ansiau D, Marquie JC. Shiftwork experience, age andcognitive performance. Ergonomics 2005;48:1282–93.

123. Cho K. Chronic ’jet lag’ produces temporal lobe atrophy and spatialcognitive deficits. Nat Neurosci 2001;4:567–8.

124. Menezes MC, Pires ML, Benedito-Silva AA, Tufik S. Sleep parameters amongoffshore workers: an initial assessment in the Campos Basin, Rio De Janeiro,Brazil. Chronobiol Int 2004;21:889–97.

125. Knutsson A, Hammar N, Karlsson B. Shift workers’ mortality scrutinized.Chronobiol Int 2004;21:1049–53.

126. Hahn RA. Profound bilateral blindness and the incidence of breast cancer.Epidemiology 1991;2:208–10.

127. Feychting M, Osterlund B, Ahlbom A. Reduced cancer incidence among theblind. Epidemiology 1998;9:490–4.

128. Pukkala E, Ojamo M, Rudanko SL, Stevens RG, Verkasalo PK. Does incidenceof breast cancer and prostate cancer decrease with increasing degree ofvisual impairment. Cancer Causes Control 2006;17:573–6.

129. Rogot E, Goldberg ID, Goldstein H. Survivorship and causes of death amongthe blind. J Chronic Dis 1966;19:179–97.

130. Asplund R, Ejdervik Lindblad B. The development of sleep in personsundergoing cataract surgery. Arch Gerontol Geriatr 2002;35:179–87.

131. Leger D, Guilleminault C, Defrance R, Domont A, Paillard M. Prevalence ofsleep/wake disorders in persons with blindness. Clin Sci (Lond) 1999;97:193–9.

132. Kellner M, Yassouridis A, Manz B, Steiger A, Holsboer F, Wiedemann K.Corticotropin-releasing hormone inhibits melatonin secretion in healthyvolunteers–a potential link to low-melatonin syndrome in depression?Neuroendocrinology 1997;65:284–90.

133. Liu RY, Unmehopa UA, Zhou JN, Swaab DF. Glucocorticoids suppress vaso-pressin gene expression in human suprachiasmatic nucleus. J Steroid Bio-chem Mol Biol 2006;98:248–53.

134. Spath-Schwalbe E, Hansen K, Schmidt F, Schrezenmeier H, Marshall L,Burger K, et al. Acute effects of recombinant human interleukin-6 onendocrine and central nervous sleep functions in healthy men. J ClinEndocrinol Metab 1998;83:1573–9.

135. Vgontzas AN, Bixler EO, Lin HM, Prolo P, Mastorakos G, Vela-Bueno A, et al.Chronic insomnia is associated with nyctohemeral activation of the hypo-thalamic-pituitary-adrenal axis: clinical implications. J Clin EndocrinolMetab 2001;86:3787–94.

136. Rodenbeck A, Hajak G. Neuroendocrine dysregulation in primary insomnia.Rev Neurol (Paris) 2001;157:S57–61.

137. Leonard BE. The HPA and immune axes in stress: the involvement of theserotonergic system. Eur Psychiatry 2005;20(Suppl. 3):S302–6.

138. Herbert J, Goodyer IM, Grossman AB, Hastings MH, de Kloet ER,Lightman SL, et al. Do corticosteroids damage the brain? J Neuroendocrinol2006;18:393–411.

139. Wirtz PH, von Kanel R, Emini L, Ruedisueli K, Groessbauer S, Maercker A,et al. Evidence for altered hypothalamus-pituitary-adrenal axis functioningin systemic hypertension: Blunted cortisol response to awakening andlower negative feedback sensitivity. Psychoneuroendocrinology 2007;32:430–6.



ARTICLE IN PRESS

140. Singh RB, Kartik C, Otsuka K, Pella D, Pella J. Brain-heart connection and therisk of heart attack. Biomed Pharmacother 2002;56(Suppl. 2):257s–65s.

141. Whitworth JA, Williamson PM, Mangos G, Kelly JJ. Cardiovascular conse-quences of cortisol excess. Vasc Health Risk Manag 2005;1:291–9.

142. Van Cauter E, Plat L, Leproult R, Copinschi G. Alterations of circadianrhythmicity and sleep in aging: endocrine consequences. Horm Res1998;49:147–52.

143. Miller DB, O’Callaghan JP. Neuroendocrine aspects of the response to stress.Metabolism 2002;51:5–10.

144. Zhou JN, Liu RY, van Heerikhuize J, Hofman MA, Swaab DF. Alterations inthe circadian rhythm of salivary melatonin begin during middle-age. JPineal Res 2003;34:11–6.

145. Schernhammer ES, Hankinson SE. Urinary melatonin levels and post-menopausal breast cancer risk in the nurses’ health study cohort. CancerEpidemiol Biomarkers Prev 2009;18:74–9.

146. Danilenko KV, Plisov IL, Wirz-Justice A, Hebert M. Human retinal lightsensitivity and melatonin rhythms following four days in near darkness.Chronobiol Int 2009;26:93–107.

147. Asplund R, Henriksson S, Johansson S, Isacsson G. Nocturia and depression.BJU Int 2004;93:1253–6.

148. Ancoli-Israel S, Cooke JR. Prevalence and comorbidity of insomnia andeffect on functioning in elderly populations. J Am Geriatr Soc 2005;53:S264–71.

149. Kobayashi R, Kohsaka M, Fukuda N, Sakakibara S, Honma H, Koyama T.Effects of morning bright light on sleep in healthy elderly women.Psychiatry Clin Neurosci 1999;53:237–8.

150. Hood B, Bruck D, Kennedy G. Determinants of sleep quality in the healthyaged: the role of physical, psychological, circadian and naturalistic lightvariables. Age Ageing 2004;33:159–65.

151. Campbell SS, Dawson D, Anderson MW. Alleviation of sleep maintenanceinsomnia with timed exposure to bright light. J Am Geriatr Soc 1993;41:829–36.

152. Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, VanSomeren EJ. Effect of bright light and melatonin on cognitive andnoncognitive function in elderly residents of group care facilities:a randomized controlled trial. JAMA 2008;299:2642–55.

153. Fetveit A, Skjerve A, Bjorvatn B. Bright light treatment improves sleep ininstitutionalised elderly–an open trial. Int J Geriatr Psychiatry 2003;18:520–6.

154. Asplund R, Lindblad BE. Sleep and sleepiness 1 and 9 months after cataractsurgery. Arch Gerontol Geriatr 2004;38:69–75.

155. Kohsaka M, Kohsaka S, Fukuda N, Honma H, Sakakibara S, Kawai I, et al.Effects of bright light exposure on heart rate variability during sleep inyoung women. Psychiatry Clin Neurosci 2001;55:283–4;

155a. Bonnet MH, Arand DL. Hyperarousal and insomnia: State of the science(epub). Sleep Med Rev; 2009.

156. Steriade M. Slow-wave sleep: serotonin, neuronal plasticity, and seizures.Arch Ital Biol 2004;142:359–67.

*157. Vgontzas AN, Chrousos GP. Sleep, the hypothalamic-pituitary-adrenal axis,and cytokines: multiple interactions and disturbances in sleep disorders.Endocrinol Metab Clin North Am 2002;31:15–36.

158. Grandner MA, Kripke DF, Langer RD. Light exposure is related to social andemotional functioning and to quality of life in older women. Psychiatry Res2006;143:35–42.

159. Rao ML, Muller-Oerlinghausen B, Mackert A, Strebel B, Stieglitz RD, Volz HP.Blood serotonin, serum melatonin and light therapy in healthy subjects andin patients with nonseasonal depression. Acta Psychiatr Scand1992;86:127–32.

160. Gould E. Serotonin and hippocampal neurogenesis. Neuropsychopharmacology1999;21:46S–51S.

161. Koller G, Bondy B, Preuss UW, Zill P, Soyka M. The C(-1019)G 5-HT1Apromoter polymorphism and personality traits: no evidence for significantassociation in alcoholic patients. Behav Brain Funct 2006;2:7.

162. Glickman G, Byrne B, Pineda C, Hauck WW, Brainard GC. Light therapy forseasonal affective disorder with blue narrow-band light-emitting diodes(LEDs). Biol Psychiatry 2006;59:502–7.

163. McEnany GW, Lee KA. Effects of light therapy on sleep, mood, andtemperature in women with nonseasonal major depression. Issues MentHealth Nurs 2005;26:781–94.

164. Park SJ, Tokura H. Bright light exposure during the daytime affects circadianrhythms of urinary melatonin and salivary immunoglobulin A. ChronobiolInt 1999;16:359–71.

165. Hashimoto S, Kohsaka M, Nakamura K, Honma H, Honma S, Honma K.Midday exposure to bright light changes the circadian organization ofplasma melatonin rhythm in humans. Neurosci Lett 1997;221:89–92.


166. Kanikowska D, Hirata Y, Hyun K, Tokura H. Acute phase proteins, bodytemperature and urinary melatonin under the influence of bright and dimlight intensities during the daytime. J Physiol Anthropol Appl Human Sci2001;20:333–8.

167. Wakamura T, Tokura H. Influence of bright light during daytime on sleepparameters in hospitalized elderly patients. J Physiol Anthropol Appl HumanSci 2001;20:345–51.

168. Nicklas MH, Bailey GB. Analysis of the Performance of Students of DaylitSchools. Washington, D.C.: Education Resources Information Center, U.S.Department of Education; 1996.

169. Edwards L, Torcellini P. A Literature Review of the Effects of Natural Light onBuilding Occupants. Golden, Colorado: National Renewable Energy Labo-ratory. U.S. Department of Energy; 2002.

170. Keep PJ. Stimulus deprivation in windowless rooms. Anaesthesia1977;32:598–602.

171. Yamadera H, Ito T, Suzuki H, Asayama K, Ito R, Endo S. Effects of bright lighton cognitive and sleep-wake (circadian) rhythm disturbances in Alzheimer-type dementia. Psychiatry Clin Neurosci 2000;54:352–3.

172. Van Der Werf YD, Altena E, Schoonheim MM, Sanz-Arigita EJ, Vis JC, DeRijke W, et al. Sleep benefits subsequent hippocampal functioning. NatNeurosci 2009;12:122–3.

173. Okawa M, Mishima K, Hishikawa Y, Hozumi S, Hori H, Takahashi K. Circa-dian rhythm disorders in sleep-waking and body temperature in elderlypatients with dementia and their treatment. Sleep 1991;14:478–85.

174. Martin JL, Webber AP, Alam T, Harker JO, Josephson KR, Alessi CA. Daytimesleeping, sleep disturbance, and circadian rhythms in the nursing home. AmJ Geriatr Psychiatry 2006;14:121–9.

175. Jacobs D, Ancoli-Israel S, Parker L, Kripke DF. Twenty-four-hour sleep-wakepatterns in a nursing home population. Psychol Aging 1989;4:352–6.

176. Gonzalez MM, Aston-Jones G. Circadian regulation of arousal: role of thenoradrenergic locus coeruleus system and light exposure. Sleep 2006;29:1327–36.

177. Lovell BB, Ancoli-Israel S, Gevirtz R. Effect of bright light treatment onagitated behavior in institutionalized elderly subjects. Psychiatry Res1995;57:7–12.

178. Fontana Gasio P, Krauchi K, Cajochen C, Someren E, Amrhein I, Pache M,et al. Dawn-dusk simulation light therapy of disturbed circadian rest-activity cycles in demented elderly. Exp Gerontol 2003;38:207–16.

179. Mainster MA. The spectra, classification, and rationale of ultraviolet-protective intraocular lenses. Am J Ophthalmol 1986;102:727–32.

*180. Mainster MA, Turner PL. Blue-blocking IOLs Decrease Photoreceptionwithout Providing Significant Photoprotection (epub). Surv Ophthalmol;2009.

181. Chew EY, Sperduto RD, Milton RC, Clemons TE, Gensler GR, Bressler SB,et al. Risk of Advanced Age-Related Macular Degeneration after CataractSurgery in the Age-Related Eye Disease Study AREDS Report 25. Ophthal-mology 2009;116:297–303.

182. Gallin PF, Terman M, Reme CE, Rafferty B, Terman JS, Burde RM. Ophthal-mologic examination of patients with seasonal affective disorder, beforeand after bright light therapy. Am J Ophthalmol 1995;119:202–10.

183. Mainster MA, Turner PL. Retinal injuries from light: mechanisms, hazardsand prevention, Chapter 109. In: Ryan SJ, Hinton DR, Schachat AP, Wil-kinson P, eds. Retina, 4th Edition. 2 vol. 4th ed. London: Elsevier Publishers;2006:1857–1870.

184. Mainster MA, Boulton M. Retinal phototoxicity, Chapter 174. In: Albert DM,Miller JW, Blodi BA, Azar DT, editors. Principles and Practice of Ophthal-mology. 3rd ed. London, UK: Elsevier; 2008. p. 2195–205.

185. Mainster MA, Ham Jr WT, Delori FC. Potential retinal hazards. Instrumentand environmental light sources. Ophthalmology 1983;90:927–32.

186. McCarty CA, Taylor HR. A review of the epidemiologic evidence linkingultraviolet radiation and cataracts. Dev Ophthalmol 2002;35:21–31.

187. Brainard GC, Rollag MD, Hanifin JP. Photic regulation of melatonin inhumans: ocular and neural signal transduction. J Biol Rhythms 1997;12:537–46.

188. Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containingretinal ganglion cells: architecture, projections, and intrinsic photosensi-tivity. Science 2002;295:1065–70.

189. Bullough JD, Rea MS, Figueiro MG. Of mice and women: light as a circa-dian stimulus in breast cancer research. Cancer Causes Control2006;17:375–83.

190. Hankins MW, Peirson SN, Foster RG. Melanopsin: an exciting photopig-ment. Trends Neurosci 2008;31:27–36.

191. Lockley SW, Brainard GC, Czeisler CA. High sensitivity of the humancircadian melatonin rhythm to resetting by short wavelength light. J ClinEndocrinol Metab 2003;88:4502–5.


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